PAK1 regulates ATXN1 levels providing an opportunity to modify its toxicity in spinocerebellar ataxia type 1.

Spinocerebellar ataxia type 1 (SCA1) is caused by the expansion of a trinucleotide repeat that encodes a polyglutamine tract in ataxin-1 (ATXN1). The expanded polyglutamine in ATXN1 increases the protein's stability and results in its accumulation and toxicity. Previous studies have demonstrated that decreasing ATXN1 levels ameliorates SCA1 phenotypes and pathology in mouse models. We rationalized that reducing ATXN1 levels through pharmacological inhibition of its modulators could provide a therapeutic avenue for SCA1. Here, through a forward genetic screen in Drosophila we identified, p21-activated kinase 3 (Pak3) as a modulator of ATXN1 levels. Loss-of-function of fly Pak3 or Pak1, whose mammalian homologs belong to Group I of PAK proteins, reduces ATXN1 levels, and accordingly, improves disease pathology in a Drosophila model of SCA1. Knockdown of PAK1 potently reduces ATXN1 levels in mammalian cells independent of the well-characterized S776 phosphorylation site (known to stabilize ATXN1) thus revealing a novel molecular pathway that regulates ATXN1 levels. Furthermore, pharmacological inhibition of PAKs decreases ATXN1 levels in a mouse model of SCA1. To explore the potential of using PAK inhibitors in combination therapy, we combined the pharmacological inhibition of PAK with MSK1, a previously identified modulator of ATXN1, and examined their effects on ATXN1 levels. We found that inhibition of both pathways results in an additive decrease in ATXN1 levels. Together, this study identifies PAK signaling as a distinct molecular pathway that regulates ATXN1 levels and presents a promising opportunity to pursue for developing potential therapeutics for SCA1.

RAS-MAPK-MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1.

Many neurodegenerative disorders, such as Alzheimer's, Parkinson's and polyglutamine diseases, share a common pathogenic mechanism: the abnormal accumulation of disease-causing proteins, due to either the mutant protein's resistance to degradation or overexpression of the wild-type protein. We have developed a strategy to identify therapeutic entry points for such neurodegenerative disorders by screening for genetic networks that influence the levels of disease-driving proteins. We applied this approach, which integrates parallel cell-based and Drosophila genetic screens, to spinocerebellar ataxia type 1 (SCA1), a disease caused by expansion of a polyglutamine tract in ataxin 1 (ATXN1). Our approach revealed that downregulation of several components of the RAS-MAPK-MSK1 pathway decreases ATXN1 levels and suppresses neurodegeneration in Drosophila and mice. Importantly, pharmacological inhibitors of components of this pathway also decrease ATXN1 levels, suggesting that these components represent new therapeutic targets in mitigating SCA1. Collectively, these data reveal new therapeutic entry points for SCA1 and provide a proof-of-principle for tackling other classes of intractable neurodegenerative diseases.

Epidemiology, management, and economic impact of acute myeloid leukemia and myelodysplastic syndrome in Spain at the hospital level: a claims database analysis.

OBJECTIVES: This study reviewed patient characteristics, management, and medical costs of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs) in Spanish hospitals. METHODS: Data were extracted from the Spanish Ministry of Health records via a claims database containing patient records from 192 private and 313 public hospitals between 1997 and 2015 for AML, and 2008 and 2015 for MDS. Direct medical costs at the hospital level were calculated based on mean medical procedure costs determined per the Spanish Ministry of Health. RESULTS: Records for 39,568 patients with AML and 33,091 with MDS were analyzed. The median age of AML patients was 65 years (interquartile range (IQR) = 27) and of MDS patients was 81 years (IQR = 12). In terms of disease management, 58% and 83% of admissions were due to emergencies for patients with AML and MDS, respectively; median length of hospital stay was 14 days (IQR = 25) for AML and seven days (IQR = 9) for MDS. There was an increase in allogeneic hematopoietic stem cell transplantations over time for patients with AML or MDS. Mean annual direct medical costs of AML and MDS, respectively, were €66,422,245 and €42,635,313 for total costs, and €30,775 and €10,312 per patient. Of the total costs, transplantations contributed total annual costs of €15,843,982 and €2,705,791 for patients with AML and MDS, respectively. CONCLUSIONS: This study provides novel data to assist decision makers in allocating resources. AML and MDS represent a significant burden for the National Spanish Healthcare System, with substantial costs incurred in secondary care, principally associated with the increasing number of transplantations.

High-Throughput Functional Analysis Distinguishes Pathogenic, Nonpathogenic, and Compensatory Transcriptional Changes in Neurodegeneration.

Discriminating transcriptional changes that drive disease pathogenesis from nonpathogenic and compensatory responses is a daunting challenge. This is particularly true for neurodegenerative diseases, which affect the expression of thousands of genes in different brain regions at different disease stages. Here we integrate functional testing and network approaches to analyze previously reported transcriptional alterations in the brains of Huntington disease (HD) patients. We selected 312 genes whose expression is dysregulated both in HD patients and in HD mice and then replicated and/or antagonized each alteration in a Drosophila HD model. High-throughput behavioral testing in this model and controls revealed that transcriptional changes in synaptic biology and calcium signaling are compensatory, whereas alterations involving the actin cytoskeleton and inflammation drive disease. Knockdown of disease-driving genes in HD patient-derived cells lowered mutant Huntingtin levels and activated macroautophagy, suggesting a mechanism for mitigating pathogenesis. Our multilayered approach can thus untangle the wealth of information generated by transcriptomics and identify early therapeutic intervention points.

Effect of the DTwP Haemophilus influenzae b conjugate vaccination in Mexico (1999-2007).

The introduction of type b Haemophilus influenzae (Hi b) conjugate vaccines for children as part of immunization schedules has led to a sharp drop in the incidence of Hi b disease. In 1999, the Haemophilus influenzae b DTwP-HB/Hi b vaccine was introduced into the primary immunization program in Mexico. There have been no studies evaluating the vaccine after the widespread immunization in our country. The immune response to Hi b vaccines in different countries varies both quantitatively and qualitatively. Replacement of Hi b strains is expected between pre- and post-vaccination eras. Documentation on these three aspects will be useful for decisions regarding the use of the vaccine. In this review, we show and discuss the potential benefits of vaccination with DTwP-HB/Hi b in Mexico in terms of our collected data obtained during the last 8 years on population genotype variations and on concentration and avidity of IgG antibodies. As the epidemiological follow-up data are missing, the evaluation of the results of these three types of studies, as a whole, allows clarification of the scenario of the protection after vaccination in Mexico, in absence of the drop in cases reports. These results reinforce the findings of postvaccination studies done elsewhere.

Aspectos demográficos, estado de salud y necesidades expresadas en consultantes al servicio de geriatría del Hospital de Apoyo No. 2 IPSS Yanahuara

La población total de adultos mayores encuestados del servicio de geriatría del Hospital de Apoyo No. 2 IPSS Yanahuara es de 424, con el 65.09 por ciento correspondiente a la tercera edad y el 34.91 por ciento a la cuarta edad, según sexo, el 35.38 por ciento son varones y el 64.62 por ciento son mujeres. Los varones tienen la condición de casados en el 77.65 por ciento, en comparación con el 49.9 por ciento de mujeres. El sexo femenino predomina cuando se analiza la solteria y viudez (con el 13.0 por ciento - 2.0 por ciento y el 36.55 por ciento - 17.4 por ciento respectivamente). Cerca de 6 veces más las mujeres tienen la condición de analfabetos o iletrados. Las mujeres, igualmente, tienen predominancia en el nivel de instrucción primaria. Cuando se toma en cuenta el nivel secundario no hay mayores diferencias. En el nivel superior los varones predominan. Conforme aumenta la edad disminuye el nivel de instrucción. El 24.86 por ciento tiene buen estado de salud, el 29,3 por ciento tiene buena visión y el 47.8 por ciento goza de buena audición. Los varones tienen mejor estado de salud persivido y mejor visión que las mujeres. El sexo femenino tiene mejor audición. Todos estos efectos de salud disminuyen con la edad. El 84.4 por ciento usa medicamentos. Requiere apoyo médico el 97.5 por ciento de la población encuestada aproximadamente dos tercios de la población encuestada es totalmente valida. La continencia de esfinteres es la más afectada y la función de alimentarse con total independencia es la menos afectada. El 11.94 por ciento de la población de adultos mayores no toma decisiones con facilidad; el 36.1 por ciento tiene dificultad para recordar, el 30.5 por ciento se siente triste. Tiene pareja el 60.85 por ciento, se lleva bien con su pareja el 57.63 por ciento y es sexualmente activo el 16.98 por ciento. El 68.40 por ciento recibe una pensión como tipo de ingreso, el 12.89 por ciento tiene trabajo independiente, el 10.03 por ciento elingreso es familiar. El 8.37 por ciento vive solo, el 37.26 por ciento vive en una unidad familiar simple, el 47.45 por ciento vive en una unidad familiar compleja y el 6.92 por ciento vive con otros familiares. La alimentación, el vestido, la vivienda, atención en casa cuando se enferma, ocupa bien su tiempo libre tienen porcentajes de estar satisfechos por encima del 90.0 por ciento. Tiene necesidad de efecto y ayuda para resolver problemas cerca de la mitad de los encuestados. Sólo el 48.09 por ciento frecuenta a sus amigos y el 56.77 por ciento le gustaría trabajar. Las tareas del hogar, estar en casa ver TV, son las necesidades de tiempo libre internas más comunes; leer libros, periódicos y cuidar niños le siguen en frecuencia. El trabajo voluntario ayuda familiar, reunirse con familiares, pasear por las calles son las más frecuentes actividades de tiempo libre externos; le siguen en frecuencia ira fuertas, a un club de tercera edad, trabajo remunerado, asistir a espectáculos y otras actividades. La mejora de pensión y la asistencia médica son los requerimientos preferidos; tener alguna actividad recreativa, disfrutar unas vacaciones, tener un trabajo remunerado, asistiendo a club de tercera edad y una persona que le cuida en casa le siguen en frecuencias.